Pharmacogenet Genomics 2012 Nov;22(11):796-802
Department of Statistics, North Carolina State University, Raleigh, North Carolina 27695-7566, USA.
Objective: Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.
Methods: In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.
Results: Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.
Conclusion: The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.